HLA-DQ8 and DRB1*0401 molecules render humans and transgenic mice susceptible to develop arthritis while DRB1*0402 provide protection. Collagen-induced arthritis (CIA) susceptible HLA transgenic mice produce rheumatoid factor and anti-cyclic citrullinated peptide antibodies (ACPA) similar to that in patients.. However, not 100% of humans and mice inheriting DR4 develop arthritis suggesting other genetic and environmental factors that may be involved in precipitation of disease. Epidemiological studies in humans have suggested smoking as a major environmental risk factor for seropositive RA. Smoking has been suggested to increase severity and extra-articular features of RA in the presence of *0401 molecules. However, the mechanism by which smoking modulates immune response leading to increased severity and higher production of ACPA is unknown. Clinical studies have suggested that ACPA precede onset of clinical symptoms of RA suggesting autoimmunity starts much earlier that the actual onset of clinical disease. Smoking has been shown to increase peptidylarginine deiminase (PAD) enzymes in lungs. PADs are required for citrullination process. These observations suggest that immune response that leads to citrullination of self- proteins in arthritis may not necessarily start in synovium. However, this effect of smoking has not been observed in all studies suggesting another mechanism by which smoking can impact immune response. Smokers show an increased number of activated T cells expressing HLA-DR with suppressed function of DCs. The transgenic mice proposed in this model express HLA class II molecules in a subset of CD3+T cells unlike mice but similar to that of humans. Our pilot studies using transgenic mice showed that DQ8 mice develop arthritis with earlier onset and increased severity in mice exposed to cigarette smoke compared to controls, although this effect was not observed in DR4 mice. These studies may rationalize the differences observed in human study cohorts from Europe and USA. We hypothesize that smoking may increase disease severity by modulating immune response in lungs leading to presentation of a self protein like Vimentin ensuing autoreactive response. In this proposal, we have 2 aims. In aim 1 we will study the Impact of smoking on pathogenesis of arthritis using transgenic mice, DRB1*0401, DQ8 and DR4/DQ, to determine interaction between MHC genes and environmental factors. We will study T cell response to self protein, Vimentin an autoantigen in RA, to understand if smoking leads to break in tolerance to self-protein. In aim2,we will study the mechanism of modulation of immune response after exposure to smoking in context of RA susceptible and resistant HLA allele and arthritis. The model described here develops arthritis with similarities to human disease in sex-bias, autoantibody profile and pathology. There are no animal studies in literature on the interaction of HLA genes and environmental factors in arthritis. The human studies suggest a role of smoking and arthritis but are controversial and lack mechanism by which environmental factors associate with genetics due to linkage of DR and DQ alleles in humans. Definition of environmental factors in context of certain genetic factors may lead to earlier intervention and educating patients resulting in a better quality of life. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis is a disabling disease that leads to joint destruction. Family studies have suggested role of genetic factors in predisposition to develop arthritis. Human studies suggest that it is a multifactorial disease requiring interaction between both genetic and environmental factors. To date there is no specific environmental factor that has been associated with arthritis. Recent studies suggest smoking as a risk factor for arthritis. In this study we will use mice that express human arthritis associated genes to delineate the role of smoking in arthritis. These humanized mice mimic rheumatoid arthritis in pathology and autoantibodies. Arthritic mice produce autoantibodies like rheumatoid factor and anti-cyclic citrullinated peptide antibodies that are used for diagnosis of rheumatoid arthritis. These studies will identify if certain genes make individuals more susceptible to the effects of smoking so that an earlier intervention can be done to avoid joint deformities.